per
WORLD INTELLECTUAL PROPERTY ORGANIZATION
International Bureau
INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCI)
(51) Internationa] Patent Classification 4 :
A61K 39/395, C12P 21/00
Al
(11) International Publication Number: WO 89/ 06975
(43) International Publication Date: 10 August 1989 (10.08.89)
(21) International Application Number: PCT/US 89/00285
(22) International Filing Date: 30 January 1989 (30.01.89)
(31) Priority Application Number: 151,413
(32) Priority Date: 2 February 1988 (02.02.88)
(33) Priority Country: US
(71) Applicant: SCHERING BIOTECH CORPORATION
[US/US]; 901 California Avenue, Palo Alto, CA
94304-1 104 (US).
(72) Inventors: COFFMAN, Robert, L. ; 239 Echo Lane,
Portolo Valley, CA 94025 (US). DE VRIES, Jan, Eg-
bert ; 6C, chemin du Trouyllat, F-69130 Ecully (FR).
(74) Agents: BLASDALE, John, H. et al.; Schering-Plough
Corporation, One Giralda Farms, Madison, NJ
07940-1000 (US).
(81) Designated States: AT (European patent), AU, BB, BE
(European patent), BG, BJ (OAPI patent), BR, CF
(OAPI patent), CG (OAPI patent), CH (European pa
tent), CM (OAPI patent), DE (European patent), DK,
FI, FR (European patent), GA (OAPI patent), GB
(European patent), HU, IT (European patent), JP,
KP, KR, LK, LU (European patent), MC, MG, ML
(OAPI patent), MR (OAPI patent), MW, NL (Euro
pean patent), NO, RO, SD, SE (European patent),
SN (OAPI patent), SU, TD (OAPI patent), TG (OAPI
patent).
Published
With international search report.
Before the expiration of the time limit for amending the
claims and to be republished in the event of the receipt
of amendments.
(54) Title: METHOD OF REDUCING IMMUNOGLOBULIN E RESPONSES
(57) Abstract
A method of reducing immunoglobulin E responses associated with certain immune disorders is provided. The
method comprises administering an effective amount of an antagonist to human interleukin-4. Preferably the antagonist is
a blocking monoclonal antibody specific for human interleukin-4, or a fragment or binding composition derived there-
from.
FOR THE PURPOSES OF INFORMATION ONLY
Codes used to identify States party to the PCT on the front pages of pamphlets publishing international appli-
cations under the PCT.
AT
Austria
FR
France
ML
Mali
AU
Australia
GA
Gabon
MR
Mauritania
BB
Barbados
GB
United Kingdom
MW
Malawi
BE
Belgium
HU
Hungary
NL
Netherlands
BG
Bulgaria
rr
Italy
NO
Norway
BJ
Benin
jp
Japan
RO
Romania
BR
Brazil
KP
Democratic People's Republic
SD
Sudan
CF
Central African Republic
of Korea
SE
Sweden
CG
Congo
KB
Republic of Korea
SN
Senegal
CH
Switzerland
u
Liechtenstein
SU
Soviet Union
CM
Cameroon
LK
Sri Lanka
TD
Chad
DE
Germany, Federal Republic of
LU
Luxembourg
TG
Togo
DK
Denmark
MC
Monaco
US
United States of America
FI
Finland
MG
Madagascar
WO 89/06975
PCIYUS89/00285
METHOD OF REDUCING IMMUNOGLOBULIN E RESPONSES
The invention relates generally to a method for
treating immune disease associated with excessive
production of immunoglobulin E (IgE) and, more
particularly, to a method of reducing IgE production by
inhibiting the action of interleukin-4 .
As far as can be determined, the main
physiological function of IgE-mediated responses is to
combat parasites. The response can be divided into five
phases: an IgE-bearing B cell is stimulated to respond
to an antigen (phase 1) and activated to secrete IgE
antibodies (phase 2); the produced antibodies bind to
mast cells and basophils in tissue (phase 3, antibody
fixation), interaction of antigen with cell-bound IgE
activates these cells, and causes the release of chemical
mediators stored in their granules (phase 4, degranu-
lation); and finally, the mediators induce a complex
tissue response aimed at the elimination of nonmicrobial
parasites from the body (phase 5). Part of this defense
mechanism is an attack on the tissue that harbors the
parasite — that is, on self. To excise a parasite from a
tissue without damaging the rest of the body is an
extraordinarly delicate act. The mediators released by
activated mast cells and basophils can cause considerable
harm, even death, if released at an inappropriate time or-
WO 89/06975
PCT/US89/00285
-2-
if directed at an inappropriate target. The IgE response
must be closely controlled and quickly attenuated after
its goal has been achieved. As long as this control is
functioning there is no danger that healthy parts of the
body will be damaged, but, should the controls fail, the
beneficial reaction will turn into a harmful one. About
90 percent of all humans have no difficulty in using
their IgE only for defensive purposes; but the remaining
unlucky 10 percent carry a genetic defect of the control
mechanism that permits the stimulation of IgE responses
by antigens that have nothing to do with parasites. At
first it was thought that this defect was limited only to
humans, but similar defects were discovered later in
several other mammals. The inappropriately stimulated
IgE responses cause a plethora of diverse diseases,
grouped under the name allergy or atopy? see Klein,
Immunology; The Science of Self-Nonself Discrimination
(John Wiley & Sons, New York, 1982).
Currently glucocorticoid steroids are the most
effective drugs for treating allergic diseases. However,
prolonged steroid treatment is associated with many
deleterious side effects: Goodman and Gilman, The
Pharmacological Basis of Therapeutics, 6th Ed. (MacMillan
Publishing Company, New York, 1980). Consequently, the
availability of alternative approaches to the treatment
of immune disorders associated with excessive IgE
production could have important clinical utility.
The invention therefore provides a method of
reducing levels of IgE by administering an effective
amount of an antagonist to human interleukin-4 (IL-4). a
preferred antagonist to IL-4 is a monoclonal antibody, or
binding compositions derived therefrom by standard
techniques .
The antagonist to human interleukin-4 is
preferably a monoclonal antibody capable of blocking the
WO 89/06975
PCT/US89/0028S
-3-
immunoglobulin E enhancing activity of human interleukin-
4, a fragment of a monoclonal antibody capable of
blocking the immunoglobulin E enhancing activity of human
interleukin-4, or a binding composition comprising the
heavy chain variable region and light chain variable
region of a monoclonal antibody capable of blocking the
immunoglobulin E enhancing activity of human interleukin-
4.
The invention is based on the discovery that
IL-4 increases the production of IgE in humans. The
method of the invention therefore comprises administering
to a patient an effective, or disease-ameliorating
amount, of an antagonist to human IL-4.
Preferably, the antagonists of the invention
are derived from antibodies specific for human IL-4.
More preferably, the antagonists of the invention
comprise fragments or binding compositions specific for
IL-4.
Antibodies comprise an assembly of polypeptide
chains linked together by disulfide bridges. Two major
polypeptide chains, referred to as the light chain and
the heavy chain, make up all major structural classes
(isotypes) of antibody. Both heavy chains and light
chains are further divided into subregions referred to as
variable regions and constant regions. Heavy chains
comprise a single variable region and three different
constant regions, and light chains comprise a single
variable region (different from that of the heavy chain)
and a single constant region (different from those of the
heavy chain). The variable regions of the heavy chain
and light chain are responsible for the antibody's
binding specificity.
As used herein, the term "heavy chain variable
region" means a polypeptide (1) which is from 110 to 125
amino acids in length (the number starting from the heavy
WO 89/06975
PCT/US89/00285
-4-
chain's N-terminal amino acid), and (2) whose amino acid
sequence corresponds to that of a heavy chain of a
monoclonal antibody of the invention. Likewise , the terra
"light chain variable region" means a polypeptide (1)
which is from 95 to 115 amino acids in length (the
numbering starting from the light chain's N-terminal
amino acid), and (2) whose amino acid sequence
corresponds to that of a light chain of a monoclonal
antibody of the invention.
As used herein the term "monoclonal antibody"
refers to homogenous populations of immunoglobulin which
are capable of specifically binding to human IL-4.
As used herein the term "binding composition"
means a composition comprising two polypeptide chains (1)
which, when operationally associated, assume a
conformation having high binding affinity for human
interleukin-4, and (2) which are derived from a hybridoma
producing monoclonal antibodies specific for human
interleukin-4. The term "operationally associated" is
meant to indicate that the two polypeptide chains can be
positioned relative to one another for binding by a
variety of means, including association in a native
antibody fragment, such as Fab or Fv, or by way of
genetically engineered cysteine-containing peptide
linkers at the carboxyl termini. Normally, the two
polypeptide chains correspond to the light chain variable
region and heavy chain variable region of a monoclonal
antibody specific for human interleukin-4.
Preferably, antagonists of the invention are
derived from monoclonal antibodies specific for human
IL-4. Monoclonal antibodies capable of blocking IgE-
enhancing activity of IL-4 are selected in standard in
vitro assays for IL-4 based on T cell proliferation; e.g.
Yokota et al. (cited above). It has been observed in
murine systems that all biological activities of IL-4 can
WO 89/06975
PCT/US89/00285
-5-
be blocked by a single monoclonal antibody • Thus, it is
believed that all the activities are mediated by a single
site, i.e. the receptor binding site, on the protein.
Hybridomas of the invention are produced by
well-known techniques. Usually, the process involves the
fusion of an immortalizing cell line with a B-lymphocyte
which produces the desired antibody. Alternatively, non-
fusion techniques for generating immortal antibody-
producing cell lines are possible, and come within the
purview of the present invention; e.g. virally induced
transformation: Casali et al., "Human Monoclonals from
Antigen-Specific Selection of B Lymphocytes and
Transformation by EBV," Science , Vol. 234, pgs. 476-479
(1986). Immortalizing cell lines are usually transformed
mammalian cells, particularly myeloma cells of rodent,
bovine, or human origin. Most frequently, rat or mouse
myeloma cell lines are employed as a matter of
convenience and availability.
Techniques for obtaining the appropriate
lymphocytes from mammals injected with the target antigen
are well known. Generally, either peripheral blood
lymphocytes (PBLs) are used if cells of human origin are
desired, or spleen cells or lymph node cells are used if
non-human mammalian sources are desired. A non-human
host mammal is injected with repeated dosages of the
purified antigen, and the mammal is permitted to generate
the desired antibody-producing cells before these are
harvested for fusion with the immortalizing cell line.
Techniques for fusion are also well known in the art, and
in general involve mixing the cells with a fusing agent,
such as polyethylene glycol. Hybridomas are selected by
standard procedures, such as HAT selection. Human-human
hybridomas are especially preferred. From among these
hybridomas, those secreting the desired antibody are
selected by assaying their culture medium by standard
WO 89/06975
PCT/US89/00285
-6-
immunoassays, such as Western blotting, ELISA, RlA r or
the like. Antibodies are recovered from the medium using
standard protein purification techniques; e.g. Tijssen r
Practice and Theory of Enzyme Immunoassays (Elsevier,
Amsterdam, 1985). Many references are available for
guidance in applying any of the above techniques; e.g.
Kohler et al., Hybridoma Techniques (Cold Spring* Harbor
Laboratory, New York, (1980); Tijssen, Practice and
Theory of Enzyme Immunoassays (Elsevier, Amsterdam,
1985); Campbell, Monoclonal Antibody Technology
(Elsevier, Amsterdam, 1984); Hurrell , Monoclonal
Hybridoma Antibodies: Techniques and Applications (CRC
Press, Boca Raton, FL, 1982); and the like.
The use and generation of fragments of
antibodies is also well known, e.g. Fab fragments:
Tijssen, Practice and Theory of Enzyme Immunoassays
(Elsevier, Amsterdam, 1985); and Fv fragments. Hochman
et al., Biochemistry, Vol. 12, pgs. 1130-1135 (1973),
Sharon et al., Biochemistry , Vol. 15, pgs 1591-1594
(1976), and Ehrlich et al., U.S. Patent 4,355,023; and
antibody half -molecules : Auditore-Hargreaves , U.S.
Patent 4,470,925. Moreover, such compounds and
compositions of the invention can be used to construct
bi-specific antibodies by known techniques; e.g., further
fusions of hybridomas (i.e. to form so-called quadromas )
— see Reading, U.S. Patent 4,474,493; or chemical
reassociation of half -molecules — see Brennan et al.,
Science, Vol. 229, pgs. 81-83 (1985).
Hybridomas and monoclonal antibodies of the
invention are produced against either glycosylated or
unglycosylated versions of recombinantly-produced mature
human interleukin-4. Generally, unglycosylated versions
of human IL-4 are produced in E. coli and glycosylated
versions are produced in mammalian cell hosts, e.g. CV1
WO 89/06975
PCT/US89/00285
-7- ,
or COS monkey cells, mouse I* cells, or the like.
Recombinant ly produced mature human IL-4 is produced by
introducing an expression vector into a host cell using
standard protocols; e.g. Maniatis et al., Molecular
Cloning; A Laboratory Manual (Cold Spring Harbor
Laboratory, "New York, 1982); Okayama and Berg, Mol. Cell.
Biol, , Vol 2, pgs 161-170 (1982) and Vol. 3, pgs. 280-289
(1983); Hamer, Genetic Engineering , Vol. 2, pgs. 83-100
(1980) and U.S. Patent 4,599,308; Kaufman et al., Mol.
Cell. Biol. , Vol. 2, pgs. 1304-1319 (1982); or the like.
Construction of bacterial or mammalian
expression vectors is well known in the art, once the
nucleotide sequence encoding a desired protein is known
or otherwise available; e.g. DeBoer in U.S. Patent
4,551,433 discloses promoters for use in bacterial
expression vectors; Goeddel et al. in U.S. Patent
4,601,980, and Riggs in U.S. Patent 4,431,739 disclose
the production of mammalian proteins by E. coli
expression systems; and Riggs (cited above), Ferretti et
al., Proc. Natl. Acad. Sci. , Vol. 83, pgs 599-603 (1986),
Sproat et al., Nucleic Acids Research , Vol. 13, pgs.
2959-2977 (1985), and Mullenbach et al., J. Biol. Chem. ,
Vol. 261, pgs. 719-722 (1986) disclose how to construct
synthetic genes for expression in bacteria. Accordingly,
these references are incorporated by reference. The
amino acid sequence of mature human IL-4 is disclosed by
Yokota et al. (cited above) , and the cDNA encoding human
IL-4 carried by the pcD vector described by Yokota et al.
(cited above) is deposited with the American Type Culture
Collection (ATCC) , Rockville, MD, under accession number
67029. Many bacterial expression vectors and hosts are
available commercially and through the ATCC. Preferably,
human IL-4 for immunizing host animals is isolated from
culture supernatants of COS, CV1, or mouse L cells which
have been transiently transfected by the above-mentioned
pcD vector.
WO 89/06975
PCT/US89/00285
-8-
Antibodies and antibody fragments charac-
teristic of hybridoraas of the invention can also be
produced by recombinant means by extracting messenger
RNA, constructing a cDNA library, and selecting clones
which encode segments of the antibody molecule; e.g. Wall
et al " Nucleic Acids Research. Vol. 5, pgs. 3113-3128
(1978); Zakut et al., Nucleic Acids Research , vol 8
pgs. 3591-3601 (1980); Cabilly et al., Proc. Natl. aL.
ScK, vol. 81, pgs. 3273-3277 (1984); Boss et al. ,
Nucleic Acids Research, Vol. 12, pgs. 3791-3806 (1984),
Amster et al., Nucleic Acids Research . Vol. 8, pgs. 2055-
2065 (1980); and Moore et al., U.S. Patent 4,642,334. in
particular, such techniques can be used to produce
interspecific monoclonal antibodies, wherein the binding
region of one species is combined with a non-binding
region of the antibody of another species to reduce
immunogenicity; e.g. Liu et al., Proc. Natl. Acad. Sci . .
Vol. 84, pgs. 3439-3443 (1987).
Antagonists of the invention are administered
as a pharmaceutical composition. Such compositions
contain a therapeutic amount of at least one of the
monoclonal antibodies of the invention, or fragments
thereof, in a pharmaceutical^ effective carrier. A
pharmaceutical carrier can be any compatible, non-toxic
substance suitable for delivering the compositions of the
invention to a patient. Sterile water, alcohol, fats,
waxes, and inert solids may be included in a carrier.'
Pharmaceutical^ accepted adjuvants (e.g., buffering'
agents, dispersing agents) may also be incorporated into
the pharmaceutical composition. Generally, compositions
useful for parenteral administration of such drugs are
well known, e.g. see Remington's Pharmaceutical Science ,
15th Ed. (Mack Publishing Company, Easton, PA 1980).
Alternatively, compositions of the invention may be
introduced into a patient's body by implantable drug
WO 89/06975
PCT/US89/00285
-9-
delivery system; e.g. see Urquhart et al., Ann. Rev.
Pharmacol. Toxicol.. Vol. 24, pgs. 199-236 (1984).
When the antagonists of the invention are
derived from antibodies, they are normally administered
parenterally, preferably intravenously. Since such
protein- or peptide-antagonists may be immunogenic, they
are preferably administered slowly, either by a con-
ventional IV administration set or from a subcutaneous
depot.
When administered parenterally, the antibodies
or fragments will normally be formulated with a
pharmaceutical^ acceptable parenteral vehicle in a unit
dosage form suitable for injection (solution, suspension,
emulsion) . Such vehicles are inherently nontoxic and
nontherapeutic. Examples of such vehicles are normal
saline, Ringer's solution, dextrose solution, and Hank's
solution. Nonaqueous vehicles such as fixed oils and
ethyl oleate may also be used. A preferred vehicle is 5%
dextrose/saline. The vehicle may contain minor amounts
of additives such as substances that enhance isotonicity
and chemical stability, e.g., buffers and
preservatives. The antibody is preferably formulated in
purified form substantially free of aggregates and other
proteins at concentrations of about 5 to 30 mg/ml,
preferably 10 to 20 mg/ml. For intravenous delivery,
this may then be adjusted to a concentration in the range
of about 1 to about 20 mg/ml.
Selecting an administration regimen for an
antagonist depends on several factors, including the
serum turnover rate of the antagonist, the serum level of
IL-4 associated with the immune disorder, the
immunogenicity of the antagonist, the accessibility of
the target IL-4 (e.g. if non-serum IL-4 is to be
blocked), the affinity of IL-4 to its receptor (s)
relative to that of IL-4 to the antagonist, and the
WO 89/06975
PCT/US89/00285
-10-
like. Preferably, an administration regimen maximizes
the amount of antagonist delivered to the patient
consistent with an acceptable level of side effects*
Accordingly, the amount of antagonist delivered depends
in part on the particular antagonist and the severity of
the disease being treated. Guidance in selecting
appropriate doses is found in the literature on
therapeutic uses of antibodies; e.g. Bach et al. # chapter
22, in Perrone et al., eds., Handbook of Monoclonal
Antibodies (Noges Publications, Park Ridge, NJ, 1985);
and Russell, pgs. 303-357, and Smith et al., pgs. 365-
389, in Haber et al., eds. Antibodies in Human Diagnosis
and Therapy (Raven Press, New York, 1977). Preferably,
the dose is in the range of about 1-20 mg/kg per day,
especially when the antagonist comprises monoclonal
antibodies or Fab-sized fragments thereof (including
binding compositions) . More preferably the dose is in
the range of about 1-10 mg/kg per day.
The descriptions of the foregoing embodiments
of the invention have been presented for purpose of
illustration and description. They are not intended to
be exhaustive or to limit the invention to the precise
forms disclosed, and obviously many modifications and
variations are possible in light of the above teaching.
The embodiments were chosen and described in order to
best explain the principles of the invention and its
practical application to thereby enable others skilled in
the art to best utilize the invention in various
embodiments and with various modifications as are suited
to the particular use contemplated. It is intended that
the scope of the invention be defined by the claims
appended hereto.
WO 89/06975
PCT/US89/00285
-11-
Applicants have deposited E. coli MC1061
carrying pcD-human-IL4 with the American Type Culture
Collection, Rockville, MD, USA (ATCC) , under accession
number 67029, This deposit was made under the Budapest
Treaty (1977) on the International Recognition of the
Deposit of Micro-organisms for the purposes of Patent
Procedure.
WO 89/06975
PCT/US89/00285
-12-
WE CLAIM:
A method of reducing an immunoglobulin E
response in a person comprising administering an
effective amount of an antagonist to human inter leukin-4.
2. The method of claim 1 wherein said antagonist
to human interleukin-4 is selected from a monoclonal
antibody capable of blocking the immunoglobulin E
enhancing activity of human interleukin-4, a fragment of
a monoclonal antibody capable of blocking the
immunoglobulin E enhancing activity of human interleukin-
4. and a binding composition comprising the heavy chain
variable region and light chain variable region of a
monoclonal antibody capable of blocking the
immunoglobulin E enhancing activity of human interleukin-
4.
3. The method of claim 2 wherein said fragment of
said monoclonal antibody is an Fab fragment.
4 * The method of claim 2 wherein said monoclonal
antibody is produced by a human-human hybridoma.
5. The method of claim 4 wherein said fragment of
said monoclonal antibody is an Fab fragment.
6. The method of claim 2 wherein said step of
administering includes intravenous delivery of said
antagonist at a concentration in the range of about 1 to
20 mg/ral.
7 * The method of claim 6 wherein said step of
administering further includes intravenous delivery of an
WO 89/06975
PCT/US89/00285
-13-
amount of said antagonist in the range of about 1 to 20
mg/kg body weight of said individual per day.
8. Use of an antagonist to human interleukin-4 for
the preparation of a therapeutic composition useful in
reducing an immunoglobulin E response,
9. Use as claimed in claim 8 wherein said
antagonist to human interleukin-4 is selected from a
monoclonal antibody capable of blocking the
immunoglobulin E enhancing activity of human interleukin-
4, a fragment of a monoclonal antibody capable of
blocking the immunoglobulin E enhancing activity of human
interleukin-4, and a binding composition comprising the
heavy chain variable region and light chain variable
region of a monoclonal antibody capable of blocking the
immunoglobulin E enhancing activity of human interleukin-
4.
10. Use as claimed in claim 9 wherein said
monoclonal antibody is an Fab fragment produced by a
human-human hybridoma .
INTERNATIONAL SEARCH REPORT
I nternational Application No
L CLASSIFICATION OF SUBJECT MATTER (if several classification symbols apply, Indicate all) 6
According to International Patent Classification (IPC) or to both National Classification and IPC
Int. CI. 4 A61K39/395 ; C12P21/00
II. FIELDS SEARCHED
Minimum Docomentatioa Searched 7
Classification System
Classification Symbols
Int.Cl. 4
A61K ; C12P
Documentation Searched other than Minimum Documentation
to the Extent that such Documents are Included in the Fields Searched 6
UL DOCUMENTS CONSIDERED TO BE RELEVANT 9
Category c
Citation of Document, 11 with indication, where appropriate, of the relevant passages 12
Relevant to Claim No. 13
X,P
PROC.NATL.ACAD.SCI.USA
vol. 83, December 1986,
page 9675 - 9678; FINKELMAN F.D. et al:
"Suppression of 1n vivo polyclonal IgE responses
by Mab to the lymphokine Bcell stimulatory
factorl"
see the whole document
JOURNAL OF IMMUNOLOGY
vol. 141, no. 7, 01 October 1988, USA
page 2335 - 2341; FINKELMAN F.D.:
"IL-4 is required to generate and sustainin vivo
Ig-E responses"
see the whole document
-/--
1-10
1-10
° Special categories of dted documents : 10
'A* document defining the general state of the art which is not
considered to be of particular relevance
*E* earlier document but published on or after the International
filing date
IT document which may throw doubts on priority claim(s) or
which is dted to establish the publication date of another
dtation or other special reason (as spedfled)
*0* document referring to an oral disdosure, use, exhibition or
other means
"7* document published prior to the international filing date but
later than the priority date daimed
T" later document published after the international filing date
or priority dale and not in conflict with the application but
dted to understand the principle or theory underlying the
invention
H" document of particular relevance; the daimed invention
cannot be considered novel or cannot be considered to
involve an inventive step
"Y" document of particular rdevance; the daimed invention
cannot be considered to involve an inventive step when the
document Is combined with one or more other such docu- .
meats, such combination being obvious to a person skilled
in the art
'Si' document member of the same patent family
IV. CERTIFICATION
Date of the Actual Completion of the International Search
14 NQVFMBFR 19B9
Date of Mailing of this International Search Report
30.0189
International Searching Authority
EUROPEAiN PATEiNT OFFICE
Signature of Authorized Officer
AVEDEKIAN P.F
MITTEN
Fora PCT/ISA/210 (umd ttaet) (JaBury
nr. DOCUMENTS CONSIDERED TO BE RELEVANT (CONTINUED FROM THE SECOND SHEET)
International Application No PCT/US 89/00285
Category
Citation of Document, with indication; where appropriate, of the relevant passages
Relevant to Claim No.
A-P
A-P
NATURE
vol. 315, 23 May 1985,
page 333 - 335; OHARA J. et al:
"production of a monoclonal antibody to and
molecular characterization of Bcell stimulatory
factorl"
see the whole document
EP, A, 255547 (KISHIM0T0)
see the whole document
EP, A, 254767 (KISHIM0T0)
see the whole document
1-10
1-10
1-10
Fon PCT/ISA/210 (extra tbed) (Jaaaxy IW)
ANNEX TO THE INTERNATIONAL SEARCH REPORT pct/os 89/00285
ON INTERNATIONAL PATENT APPLICATION NO.
SA 26595
This annex lists the patent family members relating to the patent documents cited in the above-mentioned international search report.
The members are as contained in the European Patent Office EDP file on
The European Patent Office is in no way liable for these particulars which are merely given for the purpose of information. 21/04/89
Patent document
Publication
Patent family
Publication
cited in starts report
date
members)
date
EP-A-255547
10-02-88
EP-A-
AU-A-
EP-A-
JP-A-
0254767
7619187 '
0259585
63258494
03- 02-88
04- 02-88
16-03-88
25-10-88
EP-A-254767
03-02-88
EP-A-
0255547
10-02-88
AU-A-
7619187
04-02-88
EP-A-
0259585
16-03-88
JP-A-
63258494
25-10-88
For more details about this annex : see Official Journal of the European Patent Office, No. 12/8Z